The objective of this proposal is to determine if Propionibacteria are etiologically important to the development of sarcoidosis in the United States (Aim 1), and to develop a mouse model of sarcoidosis using this bacterium (Aim 2). Several lines of evidence suggest that this anaerobic bacteria may be involved in the pathogenesis of disease. First Propionibacteria have been identified by culture and PCR in a high percentage of sarcoid lymph nodes from Japanese and European patients, and studies with in situ molecular probes detected Propionibacteria within sarcoid granulomas. Second, antibiotics effective against this organism showed remarkable efficacy in a small group of patients with cutaneous sarooidosis. Finally, animals exposed to this bacterium develop granulomatous inflammation similar to sarcoidosis. In Aim 1 we will look for evidence of Propionibacteria by performing quantitative PCR, with probes specific for this organism, on DNA from granulomas obtained by laser capture microscopy from parffin-embedded samples. We will also look for Propionibacteria by in situ hybridization. Finally, we will attempt to culture the organism from tissue obtained from patients undergoing diagnostic evaluation. Cultured bacteria will be characterized from patients with acute-resolving and chronic-persistent disease to see if the bacterial factors contribute to clinical phenotype. Cultured bacteria will also be used for inoculation in mice to produce an animal model. The initiation, maintenance, and resolution of granulomatous inflammation in mice of several different strains will be assessed following exposure to Propionibacteria. These experiments will allow us to look at host factors as determinants of clinical phenotype. Multiple organs will be evaluated including the lungs, lymph nodes, liver, spleen, heart, brain, and eyes, and skin to determine whether host factors or bacterial factors are important for specific organ involvement. Future directions will include a placebo-controlled trial of tetracyclines for sarcoidosis if Propionibacteria are identified.